A series of Reynolds-averaged Navier-Stokes calculations were employed to study the performance of rocket-based combined-cycle systems operating in an all-rocket mode. This parametric series of calculations were executed within a statistical framework, commonly known as design of experiments. The parametric design space included four geometric and two flowfield variables set at three levels each, for a total of 729 possible combinations. A D-optimal design strategy was selected. It required that only 36 separate computational fluid dynamics (CFD) solutions be performed to develop a full response surface model, which quantified the linear, bilinear, and curvilinear effects of the six experimental variables. The axisymmetric, Reynolds-averaged Navier-Stokes simulations were executed with the NPARC v3.0 code. The response used in the statistical analysis was created from Isp efficiency data integrated from the 36 CFD simulations. The influence of turbulence modeling was analyzed by using both one- and two-equation models. Careful attention was also given to quantify the influence of mesh dependence, iterative convergence, and artificial viscosity upon the resulting statistical model. Thirteen statistically significant effects were observed to have an influence on rocket-based combined-cycle nozzle performance. It was apparent that the free-expansion process, directly downstream of the rocket nozzle, can influence the Isp efficiency. Numerical schlieren images and particle traces have been used to further understand the physical phenomena behind several of the statistically significant results.